PROJECT SUMMARY / ABSTRACT
Perinatal depression affects 6.5%-12.9% of mothers, with comorbid perinatal anxiety occurring in as many as
50% of cases. In low-income people of color, rates of these perinatal affective disorders (PNAD) are even higher.
PNAD are associated with adverse effects on both maternal and infant health and can contribute to preterm birth
and low birth weight. It is important to further our understanding of the etiology of PNAD to more efficaciously
identify and treat patients, especially in at-risk populations. Levels of progesterone, and its metabolites
allopregnanolone (ALLO) and pregnanolone (PA) fluctuate drastically during pregnancy and have been
implicated in the pathogenesis of PNAD. These neuroactive steroids (NAS) act via the inhibitory GABAA
receptors to alter neural circuitry and modulate affective symptoms. Postpartum withdrawal from NAS provokes
affective symptoms and modifies GABAA receptor subunit expression. Our initial published work suggests that
acute surges in NAS early in pregnancy (1st and 2nd trimesters) are also associated with affective symptoms in
low-income perinatal people of color. To our knowledge PNAD symptoms have not been studied in relation to
NAS withdrawal and surges in the same cohort. Further, our preclinical work links acute alterations in NAS to
changes in the composition of the a4, ¿2, and d GABAA receptor subunit expression, but this work has not been
translated to humans. We have developed methods to measure GABAA receptor subunit expression in peripheral
mononuclear blood cells (PBMCs). We propose to recruit 50 pregnant participants from MoMent, a longstanding
cohort comprised primarily of racial and ethnic minorities. We will measure NAS (ALLO and PA), GABAA receptor
subunit expression (a4, ¿2, and d) and affective symptoms (depression and anxiety) at four time points, once
per trimester and postpartum. Overall, we hypothesize that protracted stress common in PNAD, particularly in
people of color, may lead to exaggerated perinatal changes in NAS (Aim 1) and insufficient adaptation of
GABAAR subunits (Aim 2) contributing to high rates of PNAD. These mechanisms can occur independently or
interactively such that in some individuals, the dramatic increases in or withdrawal from NAS in the perinatal
period contribute to PNAD symptoms, especially when GABAAR do not functionally adapt to NAS. The specific
aims are to investigate (1) the association between the rate of specific perinatal NAS changes (early-pregnancy
surges, postpartum withdrawal) and affective symptoms; and (2) the association between degree of dynamic
perinatal changes in GABAA receptor subunit expression and affective symptoms, as well as to explore the
interactive effects of these two factors. By studying affective symptoms in relation to both rate of NAS
surges/withdrawal and GABAA receptor subunit expression in the same at-risk perinatal cohort, this study will
have a meaningful impact on our understanding of PNAD pathogenesis. Findings will ultimately contribute to
efforts to improve prediction, detection, and personalized treatment of PNAD symptoms – particularly in low-
income people of color who have high rates of PNAD but are under-diagnosed and under-treated.